The goal of designing isoform-selective phosphodiesterase (PDE) inhibitors with improved potency and fewer side effects has been brought one step closer following the recent publication of high-resolution crystal structures of PDEs bound to a selection of inhibitors. In a recent paper in Structure, Graeme Card et al. report that there are two conserved interactions involved in the binding of PDE inhibitors, and our understanding of these could prove valuable for the future rational design of PDE inhibitors.

PDEs affect the cellular levels of the cyclic nucleotides cAMP and cGMP, which are involved in many physiological processes such as immunity, cardiac- and smooth-muscle contraction, apoptosis, ion-channel conductance and growth control. Inhibiting these enzymes is therefore an attractive strategy in the development of smooth-muscle relaxants and drugs to treat inflammatory diseases, asthma, depression and many other diseases. In particular, there has been much interest in inhibiting the PDE4 and PDE5 isoforms. PDE4B is involved in inflammation and several inhibitors of this isoform are currently being tested in clinical trials for asthma and chronic obstructive pulmonary disease; the most famous PDE5 inhibitor drug, sildenafil (Viagra), is an effective treatment for erectile dysfunction.

However, PDE4 inhibitors cause nausea and emesis, possibly by inhibiting PDE4D in the brain, and sildenafil and related PDE5 inhibitors exhibit cross-reactivity with PDE6 and PDE11, which is thought to be responsible for side effects such as blue-tinged vision and back and muscle pain. Information about the binding mode of PDE inhibitors will therefore be crucial for the design of drugs that target these enzymes in a more selective manner.

The crystal structures of the catalytic domains of several PDEs have recently been made available. However, these structures do not shed light on the key interactions that define the common and selective features of the various inhibitors. In the new paper, Card et al. describe the co-crystal structures of PDE4B, PDE4D and PDE5A in complex with 10 known inhibitors. They reveal two common features of inhibitor binding: a planar ring structure of the inhibitor that is held in place within the enzyme active site by a pair of hydrophobic residues (a so-called hydrophobic clamp), and the formation of one or two hydrogen bonds between the inhibitor and an invariant purine-selective glutamine residue of the PDE active site.

These two features — together referred to as the Q site — define a common scaffold for PDE inhibitors. Furthermore, by looking at different inhibitors, the authors suggest that exploiting differences in the shape and hydrophobicity of the binding pockets near the invariant glutamine, and designing substituents to the inhibitor scaffold that have hydrophobic interactions with other elements of the catalytic domain, could improve both the selectivity and potency of the inhibitors.